ABSTRACT Although substance use disorder (SUD) occurs commonly in patients with schizophrenia (SCZ) and dramatically worsens their overall clinical course, the mechanisms underlying their substance use remain unknown, and new treatments to limit their substance use are needed. Our translational research program, using fMRI imaging in patients and in animals, aims to uncover mechanisms that underlie SUDs in patients with SCZ, and to facilitate strategies toward treatment development to limit their substance use. Much of this work is based on our published theoretical neurobiologic formulation suggesting that a dysfunction in the brain reward circuit (BRC) underlies substance use in SCZ, and that substances transiently ameliorate this dysfunction. Our recent study using fMRI resting state functional connectivity in patients with SCZ and cannabis use disorder provided some support for this formulation by showing that these patients have a hypoconnected BRC, which is ameliorated by use of cannabis or ?9- tetrahydrocannabinol (THC). Unfortunately, previous substance use (which, in SCZ, often begins prior to the first episode) potentially confounds interpretation of our data on BRC function in patients with SCZ. Thus, to further elucidate the potential role of BRC dysfunction in patients with SCZ-SUD, and to facilitate development of new treatments, we have turned to the neonatal ventral hippocampal lesioned (NVHL) rat, an animal model of SCZ that displays a propensity for substance use. In this R21 proposal, we begin to bridge the gap between our clinical studies and our theoretical formulation of the basis of substance use in SCZ through study of fMRI resting state functional connectivity of the BRC in the NVHL rat. In our primary aim, we seek to establish that the adult NVHL rat displays a hypoconnected BRC prior to being exposed to any substances, to provide (unconfounded) translational support that a dysregulated BRC underpins substance use in SCZ. In our secondary aim, we will explore whether: (a) cocaine, known to be preferentially self-administered by the NVHL rat; and (b) THC, shown to modulate the connectivity in patients with SCZ and cannabis use disorder, will ameliorate the dysregulated connectivity in the NVHL rat. If we are able to confirm the aims of this R21 investigation, and thus provide further support for our formulation regarding the basis of substance use in SCZ, in subsequent studies, we can begin to utilize BRC connectivity in the NVHL rat as a translational biomarker to facilitate new treatment development (e.g., as a bioassay), and as a platform for mechanistic and behavioral investigations. Given the severity of SCZ, which is worsened by substance use, this research is of great public health importance.